Reductive Cyclization Research Articles

Expanding the Scope of Chemoselective Reductive Cyclization: Synthesis of Unsubstituted 9H‐Thioxanthenes and 10‐Methyl 9,10‐Dihydroacridines and Beyond

AbstractUnsubstituted 9H‐thioxanthenes are obtained from 2‐(arylthio)benzaldehydes via In(OTf)3‐catalyzed chemoselective reductive cyclization in diisopropyl ether at elevated temperature. The reaction possesses broad substrate scope, good functional group compatibility and proceeds via chemoselective reduction of thioxanthylium ion in the presence of a highly reactive arylaldehyde. Similarly, unsubstituted 10‐methyl‐9,10‐dihydroacridines are also obtained via a Bronsted acid catalyzed chemoselective reductive cyclization of 2‐(methylphenylamino)benzaldehydes in isopropanol (solvent). The reductive cyclization method can also be utilized for the synthesis of 9‐trifluormethyl containing (thio)xanthenes. Mono‐deuterated 9H‐thioxanthene is obtained in moderate yield in deuterated solvent (THF‐d8).

Harnessing the Reactivity of Nitroarene Radical Anions to Create Quinoline N‐Oxides by Electrochemical Reductive Cyclization

Electrochemical reduction of 2‐allyl‐substituted nitroarenes using a simple, undivided electrochemical cell with non‐precious electrodes to generate nitroarene radical anions was developed. The nitroarene radical anion intermediates participate in 1,5‐hydrogen atom transfer reactions to construct quinoline N‐oxides bearing aryl‐, heteroaryl‐, alkenyl‐, benzyl‐, sulfonyl‐, or carboxyl groups.

Harnessing the Reactivity of Nitroarene Radical Anions to Create Quinoline N-Oxides by Electrochemical Reductive Cyclization.

Electrochemical reduction of 2-allyl-substituted nitroarenes using a simple, undivided electrochemical cell with non-precious electrodes to generate nitroarene radical anions was developed. The nitroarene radical anion intermediates participate in 1,5-hydrogen atom transfer reactions to construct quinoline N-oxides bearing aryl-, heteroaryl-, alkenyl-, benzyl-, sulfonyl-, or carboxyl groups.

Synthesis of 2‐Substituted Bicyclo[2.1.1]Hexan‐1‐ols via SmI2‐Mediated Reductive Cyclization Reactions

AbstractThe replacement of benzene rings with saturated bioisosteric counterparts is a key priority in drug discovery programs, and disubstituted bicyclo[2.1.1]hexanes have been recognized as flexible molecular scaffolds that could act as ortho‐substituted benzene bioisosteres. In this study, we outline the synthesis of a wide range of 2‐substituted bicyclo[2.1.1]hexan‐1‐ols, which have the potential to emulate ortho‐phenolic derivatives, via SmI2‐mediated reductive cyclization reactions. The synthetic utility of this methodology was exemplified by the preparation of several saturated analogs of pharmaceutically relevant compounds.

Total Syntheses of β- and γ-Naphthocyclinones.

After half a century from their isolation in 1974, we report the first total syntheses of β- and γ-naphthocyclinones, two dimeric pyranonaphthoquinones featuring an unusual bicyclo[3.2.1]-octadienone core. The syntheses were achieved with full stereochemical control and functional group management, relying on 1) enantioselective construction of the bicyclic core by Rh-catalyzed enantioselective 1,4-addition followed by thiolate-mediated reductive cyclization, and 2) judicious design of a common chiral, non-racemic monomer unit that is capable of divergence into the donor and acceptor units, and reunion to construct the bicyclo[3.2.1]octadienone core.

5H-benzo[c]fluorene derivative exhibits antiproliferative activity via microtubule destabilization

Present study aimed at a single component cyclization of 2-benzylidene-1-tetralones for the preparation of 5H-benzo[c]fluorenes and their antiproliferative activity. This ring closure reaction underwent via reductive cyclization in the presence of a sodium borohydride-aluminium chloride system. Ten diverse 5H-benzo[c]fluorene derivatives were prepared and evaluated for antiproliferative activity against three human cancer cell lines by SRB assay. Four of these benzofluorenes exhibited significant antiproliferative effect with an IC50 > 10.75 µM. The best representative compound 21, exhibited IC50 against K562 leukemic cells at 3.27 µM in SRB assay and 7.68 µM in Soft agar colony assay. It exhibited a microtubule destabilization effect in tubulin kinetics and inhibited 82.9 % microtubule polymer mass at 10 µM concentration in Protein Sedimentation assay (Microtubule). Compound 21 exerted G0/G1 phase arrest in cell division cycle analysis in K562 cells. It also induced apoptosis in K562 cells via activation of Caspase cascade pathway. Furthermore, compound 21 also possessed anti-inflammatory activity by inhibiting TNF-α and IL-6 moderately. It exhibited significant in vivo efficacy and reduced K562 tumour in xenograft mice by 47 % at an 80 mg/kg oral dose. Further, it was found to be safe and well tolerable up to 1000 mg/kg in Swiss albino mice. Compound 21 needs to be optimized for better in vivo efficacy in rodent models for further development.

Nickel-Catalyzed Enantioselective Reductive N-Cyclization-Thiolation Reaction of Alkene-Tethered Oxime Esters and Disulfides.

Asymmetric aza-Heck cyclization and coupling reactions offer efficient access to enantioenriched N-heterocycles, yet the current studies focus primarily on sequential C-N and C-C bond formation. Herein, we report an enantioselective reductive aza-Heck cyclization followed by a C-S coupling sequence, ultimately yielding sulfide-containing enantioenriched pyrrolines. The reaction is conducted under mild conditions and tolerates broad functionalities including alkynes, phenols, anilines, amides, nitriles, and bromides.

Advances in Chiral Pincer Complexes: Insights and Applications in Catalytic Asymmetric Reactions.

Chiral pincer complexes, characterized by their rigid tridentate coordination framework, have emerged as powerful catalysts in asymmetric synthesis. This review provides a comprehensive overview of recent advancements in the development of chiral pincer-type ligands and their corresponding transition metal complexes. We highlight the latest progress in their application across a range of catalytic asymmetric reactions, including the (transfer) hydrogenation of polar and non-polar bonds, hydrophosphination, alkynylation, Friedel-Crafts reactions, enantioselective reductive cyclization of alkynyl-tethered cyclohexadienones, enantioselective hydrosilylation, as well as Aza-Morita-Baylis-Hillman reactions. The structural rigidity and tunability of chiral pincer complexes enable precise control over stereoselectivity, resulting in high enantioselectivity and efficiency in complex molecular transformations. As the field advances, innovations in ligand design and the exploration of new metal centers are expected to expand the scope and utility of these catalysts, bearing significant implications for the synthesis of enantioenriched compounds in pharmaceuticals, materials science, and beyond.

Recent Advance in the Reductive Heck Cyclization for the Formation of Five to Nine Member Rings

Abstract: Palladium-catalyzed reactions are widely used for creating carbon-carbon and carbon-heteroatom bonds, with the Heck reaction being particularly valuable for forming rings of various sizes, including mediumsized rings. Recent reports have shown the synthetic potential of intramolecular Heck reactions for assembling rings of seven or more members. While the regioselectivity of this cyclization is often unpredictable in the absence of directing groups, the reductive Heck cyclization strategy can help minimize this issue. Nickel catalysts are also valuable due to their abundance and environmentally friendly nature, playing a pivotal role in producing biologically significant carbocycles and heterocycles. The use of both Pd(0) and Ni(0) catalysts, with or without chiral ligands, has been successful in forming five to nine-member ring heterocycles and carbocycles in a simple, cost-effective manner. This review provides a comprehensive survey of the literature from the past decade on the use of reductive Heck cyclization methodology, including mechanistic details as needed.

NaBH4‐Induced Chemoselective Mechanochemical Neat Synthesis of Bio‐Active Dihydrofuran/ϵ‐Hydroxy‐α,β‐Unsaturated Esters and Synthetic Application to Isoindoles

AbstractThe synthesis of small heterocycles under neat mechanochemical conditions is of great interest in the field of drug design because most of the commercially available drugs contain at least one heterocyclic unit. The sodium borohydride (NaBH4) promoted reductive cyclization to fused dihydrofuran under grinding technique is one of the compendium additions for the clean future. The development of chemoselective reduction under silica‐gel supported conditions represents significant progress in organic synthesis, offering a versatile and efficient method for selective reduction of specific functional groups within complex molecules. Synthesis of isoindole derivatives from the chemoselective reduce product via a sustainable short synthetic pathway is another significant process of our newly developed protocol. Finally, antileishmanial investigations of our synthesized compounds establish a soft bridge between biology and chemistry.

Sequential Synthesis of Alkenylated Quinazolines Through sp3 C−H Functionalization and Their Photophysical Properties

AbstractQuinazolines are biologically potent heterocyclic compounds; however, their synthesis poses high challenges. In this present study, we have developed an inexpensive cobalt metal‐catalyzed acceptorless dehydrogenative pathway for the sequential synthesis of alkenylated quinazolines from benzhydrol via dehydrogenation, cyclization, and subsequent dehydrogenative sp3 C−H functionalization. This transformation holds potential owing to its commercially available key starting materials, good functional tolerance, moderate reaction conditions, environmental friendliness, and applicability for gram‐scale synthesis. Furthermore, the synthetic utility of the synthesized derivatives has been explored through various reactions, including reduction, halogenation, methoxylation, Michael addition, and spiro cyclization. Additionally, the photophysical properties indicate that the nitrogen atom of the synthesized derivatives readily undergoes a reversible protonation, leading to significant changes in colour. This characteristic presents an opportunity for the creation of pH sensors with colourimetric capabilities.

Bioinspired Total Synthesis of 3-epi-Junipercedrol.

A bioinspired total synthesis of 3-epi-junipercedrol, which contains a strained tricyclo[5.2.2.03,7]undecane allo-cedrane framework and five stereocenters, was accomplished via an effective anionic semipinacol rearrangement of a tricyclic cedrane mesylate. The corresponding cedrane precursor was synthesized efficiently by employing the reductive oxy-Nazarov cyclization and an intramolecular aldol condensation as the key steps. This synthetic approach provided a further evidence for the biogenetic relationship between the typical cedrane and allo-cedrane sesquiterpenoids.

Nickel‐Catalyzed Regio‐ and Stereoselective Reductive Alkylative Cyclization of 1,6‐Enynes with Alkyl Bromides

AbstractA nickel‐catalyzed reductive alkylative cyclization of 1,6‐enynes with alkyl bromides has been developed. This transformation avoids the use of stoichiometric organometallic reagents and introduces alkyl groups regio‐ and stereoselectively into the products. This method provides a platform for the synthesis of carbo‐ and heterocycles that are widely found in many natural products and biologically active molecules.

Synthesis and antibacterial activity of angular tetrahydrocycloamino [1,2-a]quinoxalin-4-one derivatives

ObjectivesThe resistance of bacteria to current antibiotics is a significant concern in treating infectious diseases, posing a strong threat to global health, food security, and development. This underscores the need for synthesizing new heterocyclic compounds as potential lead candidates in drug discovery. Quinoxalinone derivatives, known for their presence in various therapeutic agents and clinical drugs, are of particular interest. This study aimed to synthesize angular tricyclic tetrahydrocycloamino [1,2-a]quinoxalin-4-one derivatives and evaluate their antibacterial activities. Methods/analysisThe synthesis began with preparing precursors through the condensation of substituted 1-halogeno-2-nitrobenzene and cyclic amino acids in the presence of a base in ethanol, forming 2-nitrophenyl pyrrolidine/piperidine-2-carboxylic acids (acid adducts) 3a-3j. These acid adducts were then converted to amino esters 4a-4e by reacting them with thionyl chloride/ trimethylchlorosilane and methanol. Intramolecular reductive cyclization of the acid adducts or esters produced tetrahydrocycloamino [1,2-a]quinoxalin-4-ones (5a-5j) through catalytic hydrogen transfer hydrogenation. The chemical structures of the synthesized compounds were confirmed using FTIR, 1H and 13C NMR, MS, and CHN analysis. Their in vitro antibacterial activities were evaluated against ten bacterial strains using the broth microdilution method, revealing moderate to excellent activities compared to standard antibiotics streptomycin (STM) and nalidixic acid (NLD). FindingsCompound 5g demonstrated significant antibacterial activity (MIC = 15.6 μg/mL) against S. epidermidis, and compound 5c exhibited activity (MIC = 31.3 μg/mL) against S. aureus, both compared to STM and NLD. The results suggest that some of these compounds with promising antibacterial activity could serve as leads for discovering new antibacterial drugs. Novelty/improvementThe tetrahydrocycloamino [1,2-a]quinoxalin-4-ones were prepared using two methods with higher yields than previously reported, with the second method being novel for synthesizing quinoxalin-4-ones. The in vitro antibacterial studies of these compounds were reported, and substituted quinoxalin-4-ones were synthesized from N’-ethyl-N-(2-nitrophenyl)pyrrolidine-2-carboxamide 7 in good yield.

Unraveling the ability of electronically diverse 9H-carbazoles as potential fluorophores in cellular imaging applications with BSA binding affinities

In the present study, fluorophores based on 9H-carbazole have been synthesized from readily accessible 2-nitrochalcones in a single-step reductive cyclization reaction with methyl acetoacetate. The molecular geometry was confirmed based on IR, NMR and mass analysis. The ground state geometry for all the synthesized compounds was optimized using DFT-based methods to explore the localization of frontier molecular orbitals in electronically diverse carbazoles. The photophysical studies revealed a higher Stokes shift for PPM 17 due to the presence of the naphthyl group at C-1 of carbazole. The high stability of PPM14, as evidenced by high chemical hardness, prompted us to explore its BSA binding affinity using fluorescence titration, synchronous,3-D fluorescence and energy transfer analysis. The probe (PPM 14) displayed a “turn-off” response in the presence of Fe3+ ions. The less cytotoxic behavior of PPM 14, its “turn-off” fluorescence response with Fe3+, and its utility in cell imaging application establish it as a potential small organic framework-based bio-sensor.

Enantioselective Reductive Cyclization of Alkynyl-Tethered Cyclohexadienones Catalyzed by Rhodium Complexes.

Although various types of asymmetric cyclization reactions of 1,6-enynes have been established, simple asymmetric reductive cyclization remains underdeveloped. In this study, the enantioselective reductive cyclization of alkynyl-tethered cyclohexadienones (1,6-enynes) has been developed via a chiral pincer rhodium catalyst, affording cis-hydrobenzofurans and cis-hydroindoles with high enantioselectivities (90-99% ee). Furthermore, several synthetic applications and preliminary inhibitory activity studies against SARS-CoV-2 3CLpro are presented.

Total Syntheses of (±)-Acetoxymarsupellone and (±)-Marsupellins A, B, and D Enabled by a Reductive Cyclization and Semipinacol Rearrangement Strategy.

We report herein the total syntheses of three marsupellin-family sesquiterpenoids, (±)-acetoxymarsupellone and (±)-marsupellins B and D, in 14-19 steps from our known precursor, making marsupellin A also accessible from marsupellin B through a known procedure. The critical tricyclic framework bearing the challenging C7 bridgehead all-carbon quaternary center is strategically constructed through a Ti-mediated reductive cyclization and semipinacol rearrangement sequence. This study provides a general approach to the syntheses of (ent-)longipinane-type molecules.

Divergent synthesis of chromones and chromanones from diketones using an AgOTf/[Si]H system by switching hydrosilanes

A method of using AgOTf/[Si]H for the efficient and divergent synthesis of chromones and chromanones from a common substrate via reductive coupling cyclization by switching hydrosilanes has been developed. Results of mechanistic studies revealed that under Ph2MeSiH conditions, the reaction initially undergone cyclization to form chromones 2a, which can subsequently be reduced to yield chromanones 3a. When the hydrosilane was switched to Et3SiH, the reaction route stopped at chromone 2a and C2C3 could not be further reduced. This novel, mild protocol features broad functional group compatibility, high product diversity, and utility in constructing biorelevant chromone or chromanone derivatives.

Synthesis, crystal structure, Hirshfeld, DFT, molecular docking, dynamics studies, and anti-cancer activity of 1-substituted-2-(4-(diethylamino)-2-hydroxyphenyl)- 1H-benzo[d]imidazole-5-ethyl carboxylates

In our present work, a novel series of 1-substituted-2–2-(4-(diethylamino)-2-hydroxyphenyl)- 1H-benzo[d]imidazole-5-ethyl carboxylates were synthesized by an efficient “one-pot” nitro reductive cyclization method using sodium dithionite is reported as potential anticancer agents. IR, 1H & 13C NMR and Mass spectral data confirmed the synthesized compounds' structure. Compound 6a and 6j were confirmed by their single crystal XRD studies. The Hirshfeld surfaces computational method was applied to visualize and analyse the intermolecular interactions within the crystal structure. All the synthesized compounds were assessed for in vitro anticancer activity towards human lung adenocarcinoma A549 cells and breast cancer MCF-7 cell lines. Compound 6j showed a promising activity with an IC50 value 42.7 μg/mL and 89.63 μg/mL against A549 and MCF-7 cell lines respectively. The potent compounds were assessed for cytotoxicity study on human embryonic kidney HEK 293 cell line and found to be non-toxic. Also, apoptosis study indicated compound 6j induced early apoptosis in the A549 lung adenocarcinoma and MCF-7 breast cancer cells. Molecular docking and dynamic simulation studies were carried out on human estrogen receptor protein (PDB: 3ERT).

Selective Reduction of Triple Bond via Proton-Coupled Electron Transfer for the Synthesis of α,β-Unsaturated γ-Lactams.

Described herein is the development of a visible-light-induced photoredox 1,6-enyne reductive cyclization via selective reduction of a triple bond instead of an activated double bond. The selective 1,6-enyne radical cyclization/carbon═carbon double bond cleavage provided a straightforward route to structurally valuable α,β-unsaturated γ-lactams. TEMPO-trap experiments, control experiments, and DFT calculations have offered evidence supporting the possible catalytic cycle.